Preparation of phenylalanine compounds



United States Patent() 3,399,226 7/ PREPARATION- OF HENYLALANINE COMPOUNDS Walfred S. Saari, Lansdale, Pa., assignor to Merck & Co.,

Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed Oct. 22, 1965, Ser. No. 502,284 g g 9 Claims. (Cl. 260--471) ABSTRACT OF THE DISCLOSURE Phenylalanines are prepared by contacting ahydroxylated N,N-dialkylbenzylamine with a lower alkyl ester of an a-nitroa-lkanoic acid, followed by reduction of the nitro group and hydrolysis of the ester to form the a-nitro-aalkyl-fi-Khydroxylated phenyl)propionic' acid antihypertensive products. v

This invention relatesto a process for the preparation of a-methyltyrosine and nuclear substituted derivatives thereof.

Moreparticularly, it relates to a novel process for the production of a-aIkyl-fi-(Z- or 4-hydroxyphenyl)alanine andderivatives thereof in which the phenyl ring is further substituted by one or more additional substituents.

Still more particularly, the process of the present invention relates to the conversion of N,N-disubstituted benzylamines by reaction with a lower alkyl ester of an anitro lower aliphatic acid to form a novel m-alkyl-a-nitrofi-(oor p-hydroxyphenyl)propionate ester, reducing said a-nitnopropionate ester and hydrolyzing the formed amino ester to produce a-methyltyrosine and substituted derivatives thereof.

The compounds produced by the process of this inventionare important intermediates in the production of certain optically active derivatives of phenylalanine. Thus, one of the compounds produced by the process of this invention is a methyl 3 3,4 dihydroxyphenylalanine, which has been shown to be active in reducing blood pressure of warm-blooded animals. The L-isomer of amethyl-B-3,4-dihydroxyphenylalanine, otherwise known as methyldopa,'has been used in the treatment of hundreds of patients suffering from hypertension and, as such, has been sold on a commercial scale for use in such treatment. The racemic a-methyl-fi-3,4-dihydroxyphenylalanine produced by the process of the present invention is an intermediate in the preparation of the L-isomer of this compound. Conversion of the racemic compound to the optically active L-isomer can be accomplished by known methods of resolution of racemic mixtures into their optically active components.

The starting materials used in the process of my invention are N,N-dialkylbenzylamines having at least one of the dor p-positions on the benzene ring substituted by a hydroxy substituent. Thus, the starting material of the present invention can be represented by the formula:

wherein R R and R are each selected from the group consisting of-hydrogen, hydroxy, alkoxy, acyloxy, halogen and. alkyl, and the R substituents are lower alkyl substituents'containing from 1 to 6 carbon atoms or alkyl substituents included in a morpholine, piperidine or pyrrolidine ring. The remaining positions on the benzene ring may also be substituted by substituents such as 3,399,226 Patented Aug. 27, T968 hydrogen, hydroxy, alkoxy, acyloxy, halogen, alkyl; amino, alkylamino and alkylthio.

' Preferably, the compounds used as starting materials in the process of my invention are N,N-dialkylbenzylamines or the corresponding quaternary salts which have at least one hydroxyl substituent attached to the 0- or pposition of the benzene ring. Preferred compounds for use in the process of my invention, thus, are N,N-dimethylA- hydroxybenzylamine as well as the corresponding N,N- diethyl, N,N-dipropyl, N,N-di'butyl, N,N-diamyl, N,N- dihexyl, N-ethyl-Nmethyl, N-methyl-N-propyl, the N- ethyl-N-propyl derivatives, N-(4-hydroxybenzyl)mo1-pholine and the corresponding piperidine. and pyrrolidine derivatives. Likewise, the corresponding N,N-dialkyl derivatives of 3,4-dihydroxybenzylamine, 2,4-dihydroxybenzylamine, 2,5-dihydroxybenzylamine, 2,6-dihydroxybenzylamine, 2-hydroxybenzylamine and other nuclear substituted derivatives thereof may be used as starting materials in'the process of my invention. III-addition, the corresponding quaternary ammonium salts are prepared by reaction of the above-mentioned N,N-dialkylbenzylamines with an alkylhalide to form the corresponding N- trialkylbenzylammonium halide. When employing the quaternary ammonium salts as starting materials in the process of my invention, it is preferred to form the quaternary salt directly in the solvent to be used as the reaction medium. Thus, for example, in utilizing N-trimethyl-4-hydroxy benzylammonium bromide as the starting material for the process of my invention, a solution of N,N-dimethyl-4-hydroxybenzylamine in toluene is intimately contacted with an equimolar amount of methylbromide to form the desired solution of trimethyl-4-hydroxybenzylammonium bromide which can advantageously be employed as the starting material for the reaction with the selected a-nitro ester.

In accordance with the process, the N,N'dialkyl, 0- or p-hydroxybenzylamine starting material is intimately contacted in a liquid diluent with approximately an equimolar amount of an alkyl ester of a lower aliphatic carboxylic acid having an a-nitro substituent. It is preferred to carry out the reaction in the presence of a small amount of a strong base. Compounds which are satisfactory for this purpose are alkali metal alkoxides such as sodium methoxide, sodium ethoxideand the like. Alkali metal hydroxides such as sodium and potassium hydroxide, metal alkyls such as butyl lithium and hydrides such as sodium and lithium hydride are useful in the condensation of the N,N-dialkylbenzylamine with the a-nitropropionate ester.

The a-nitro ester reactant employed as one of the reactants in the first step of my process is a lower alkyl ester of an a-nitro aliphatic carboxylic acid. For use in my process, I prefer to use an ester of an a-nitro aliphatic carboxylic acid having at least two carbon atoms and up to about 6 carbon atoms. Typical esters which may effectively be employed are methyl-u-nitropropionate, ethylm-nitropropionate, propyl-a-nitropropionate, butyl-a-nitropropionate, hexyl-a-nitropropionate, heptyl a nitropropionate, and the corresponding alkyl esters of a-nitrobutanoic acid, a-nitropentanoic acid, u-nitrohexanoic acid, as well as the branched chain isomers which contain an a-hydrogen.

A liquid diluent may be employed as the reaction medium. A preferred diluent is a solvent for the reactants and is inert under the conditions of the condensation reaction. Typical examples of such solvents are aromatic hydrocarbons such as toluene, xylene or benzene, toluene being preferred; N,N-dialkylamides such as N,N-dimet-hylformamide, N,N-dimethylacetamide and tetramethylurea; di-

methylsulfoxide; alcohols such as ethanol, methanol, propanol, isopropanol and the like, as well as ethers, e.g., dioxane and tetrahyd-rofuran, and the like.

The reaction mixture of the benzylamine andnitro ester is-maintained at an elevated temperature for a .period of from 1 to 12 hours. Under the preferred conditions, using toluene as a solvent for the reaction, the reactants are heated to the reflux temperature for a period of about 8 'hours. In this manner, excellent yields of the desired intermediateproduct are formed and may be recovered by neutralization of the reaction mixture followed byprecipitation and filtration of the solid product or by extraction into a suitable solvent.

The intermediate product isolated in this manner is an alkyl ester of an a-nitro-fi-(hydroxyphenyl)alkanoic acid. By selection of the appropriate starting materials and reactants, there can be obtained as intermediates .ethyl-3- 2-,6-dichloro-4-hydroxyphenyl) -2-nitropropionate, and ethyl-3 (2-bromo-4-hydroxyphenyl) -2-nitropropionate.

In a similar manner, the methyl, propyl, butyl, amyl and hexyl esters of the correspondingly substituted butyric, pentanoic, hex'anoic and octanoic acids can be prepared.

In the next step of my process, the formed nitro ester is reduced to the corresponding amino ester. In accordance with one embodiment of my invention, the nitro ester is contacted for a brief period of time with a small amount of Raney nickel catalyst, and subsequently hydrogenated in the presence of a metal catalyst to convert the a-nitro group to an rat-amino substituent and thus produce, after hydrolysis of the ester function, the desired a-amino-a-alkyl-B-hydroxyphenylpropionic acids which are the products of the process of my invention. A particularly desirable feature of my invention is the pretreatment of the a-nitro ester with Raney nickel catalyst. When this particular treatment is applied to the compounds of my invention, the subsequent catalytic hydrogenation is carried out in excellent yields to obtain a high overall yield of the desired amino ester. The catalyst employed in the hydrogenation is preferably a noble metal catalyst. Such catalysts include platinum oxide as well as platinum or palladium deposited on alumina or charcoal. The reduction under the influence of such catalysts is carried out with great ease and is effected at about room temperature under an atmospheric or slightly greater than atmospheric pressure. The hydrogenation may also be carried out in the presence of other metallic hydrogenation catalysts such as Raney nickel and in this case higher hydrogen. pressures and temperatures are employed. Under the preferred conditions of the hydrogenation reaction, the reaction is complete in approximately 10 to hours, whereupon the catalyst is removed by filtration. The filtrate which contains the resulting amino ester is hydrolyzed to the corresponding amino acid with an acid such as aqueous hydrochloric or hydrobromic acid or an alkali such as an aqueous solution of an alkali or alkaline earth metal hydroxide, e.g., sodium hydroxide, potassium hydroxide, barium hydroxide and the like. The desired amino acid is recovered by neutralization of the reaction mixture and filtration. Among the materials which are produced in accordance with the process of my invention are a-methylp-(4-hydroxyphenyl) alanine, a-ethyl-fi-( 4-hydroxyphenyl) alanine, a-propyl-fi-(4-hydroxyphenyl)alanine, tat-methyl- 3-(3,4-dihydroxyphenyl alanine, a-ethyl-fl- 3,4-di hydroxyphenyl)alanine, and a-propyl-fi-(3,4-dihydroxyphenyl)alanine as well as the corresponding derivatives of said compounds whercin the benzene nucleus is further substituted byione or more additional hydroxy, alkoxy.,acyloxy, halo.-

gen, alkyl, amino, alkylamino and alkylthio substitueuts. In addition to the catalytic hydrogenation of the nitro ester to the corresponding amino ester, the reduction is also advantageously effected by noncatalytic methods. Thus, the reduction of the 'nitro group to an amino group is conveniently effected'in 'a'liquid reaction medium using a reducing metal such as iron, tin or zinc 'in" an acidic m'ediumsucnas hydrochloric oracetic acidfIn addition, the reduction may be effected by the use of aluminum amalgam under neutral conditions. When the reduction is carried out in a strong"acid-medinm the reduction of the amino group and the hydrolysisof the. ester are accomplished substantially simultaneously and the product isolated from the reduction mediutn is' the desired amino acid.

EXAMPLE 1 Ethyl-Z-nitro-Z-(p-hydroxybenzyl) propionate I A mixture of 2.0 g. (0.0132 mole) of N,N-dimethyl-4- hydroxybenzylamine, 2.0 g. (0.0136 mole) of ethyl anitropropionate and 10-20 mg. of 53% sodium hydride in mineral oil 'in 3 0 'ml. of toluene is heated at reflux. Nitrogen is bubbled through the reaction mixture to remove the dimethylarnine which is formed during the reaction. After 8 hours at reflux, the reaction mixture is cooled, Washed with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. After filtration, the toluene is removed under vacuum to give ethyl-2- nitro 2-(p-hydroxybenzyl)propionate. Distillation at 0.05 mm. gave an analytical sample.

EXAMPLE 2 Product N,N-dialkylhydroxya-Nitro ester benzylamine reactants reactants N,N-dimethyl-2-hydroxy- Ethyl-a-nitro- Ethyl-2-nitro2-(2- benzylamine. propionate. hydroxybenzyl) propionate. N,N-dimethyl-3,4-dido Ethyl-Z-nitro-Z-(EIA- hydroxybenzylaminc. dihydroxybenzyD- propionate. N,N dimethyl-2,4- do 1. Ethyl'2-nitro-2-(2,4- dihydroxybenzylamine. dihydroxybenzyD- propionatew N,N-dirncthyl-2,5- do Ethyl- 2-nitro-2-(2,5-

dihydroxybenzylarninc. dihydrox'ybenzyD- propionate. N,Ndimethyl-2,6- d0 Ethyl-2-nitro-2-(2,6-

dlhydroxybenzylamine. dihydroxybenzyl)' propionate. N,N-dimethyl+ Ethyl-a-nitro- Ethyl-2-nitro-244- llydroxybenzylamlne. butyrate. hydroxybenzyhi butyratet' N,N-dimethyl-3,4- do ..Ethyl-2-nitro- 2-(3,4;-

dlhydroxybenzylaminc. dihydroxybenzyl)-' Y butyrate. 1 1 N,N-dimethy1-2,4- "do"... Ethyl-2-uitro-2-(2,4-

dlhydroxybenzylamiue. dlhydroxybenzyD- butyrate. N,ll-d1methyl-2,5- do Ethyl-2-nitro-2-(2,5-

dlhydroxybeuzylamine. dihydroxybenzyD- I hutyrate. N ,N-dunethy1-2,6- do Ethyl-2-nitr0-2-(2,6- dihydroxybenzylamine. dihydroxybcuzyD- butyrate. N,N-d1ethyl-4-hydroxy- Propyl-2-uitro-' Propyl-2-nitro-2-(4- benzylamine. peutanoate. l1ydr0xybenzyl)- pentanoate. N ,N-d1ethyl-3,4- do Propyl-2-nitro-2-(3,4- dlhydroxybenzylamiuc. dihydroxybcnzyD- pentanoate. N,I}I-d1ethyl-2,4 do Propyl-2-nitro-2-(2,4-

dlhydroxybenzylaminc. dihydroxybeuzyl)- pcntanoate. N,N-d1ethyl-2,5- do lropyl-2-uitro-2-(2,5-

dihydroxybcnzylaminc. dihydroxybcnzyD- pentanoate. N,N-d1cthyl-2,6- d0.. fropyl-2-nitro-2-(2,6-

dihydroxybenzylamine. dihydroxybeuzyD- pentanoate.

a-Methyltyrosine A solutionof 1.5 g. (0.00594 mole) of ethyl-Z-nitro- 2-(p-hydroxybenzyl)propionate in 50 ml. of absolute ethanol is heated with a small amount, approximately 0.5 'g.', of Raney nickel catalyst under reflux for 1 hour; The Raney nickel is then removed by filtraton. Platinum oxide catalyst (0.1 g.)' is added to the filtrate which is then hydrogenated in a Parr apparatus at 25-30 and an initial pressure of 20-30 p.'s.i. After 20 hours, the theoretical amount of hydrogen has been taken up; The cata- 'lyst is removed by filtration, 30 'ml. of 6 N'hydr ochlor'ic acid is added and the solution concentrated under vacuum to remove most of the ethanol. The hydrolysis is completed by heating the aqueous acidsolution at 100 for 2 hours. The reaction mixtureis concentrated under vacuum, about ml. of isopropanol added to the residue and the mixture reconcentrated to dryness. Twenty -ml. of water is added and the pH of thesolution adjusted to 5.0-6.0 with diethylamine. After cooling, filtration gives 0.58 g. (50.0%) of a-methylty'rosine, M.P. 312-- 318 dec. One recrystallization from hot water gives an analytical sample, M.P. 318320 dec., which is identical with an authentic sample of a-methyltyrosine.

EXAMPLE 4 Substituted phenylalanines The products of Example 2 are each heated with a small amount of Raney nickel catalyst under reflux for one hour and, in the manner described in Example 3, each of said Raney nickel heated nitro esters is hydrogenated in the presence of platinum oxide catalyst at room temperature at about 2-3 atmospheres of hydrogen pressure and then hydrolyzed to produce the corresponding amino acids, i.e., 2-hydroxy-u-methylphenylalanine, 3,4- dihydroxy a methylphenylalanine, 2,4 dihydroxy-amethylphenylalanine, 2,5-dihydroxy a methylphenylalanine, 2,6dihydroxy a methylphenylalanine, a-et'hyltyrosine, 3,4 dihydroxy a ethylphenylalanine, 2,4- dihydroxy on ethylphenylalanine, 2,5 dihydroxy-aethylphenyl'alanine, 2,6 dihydroxy a ethylphenylalanine, u-propyltyrosin-e, 3,4-dihydroxy a propylphenylalanine, 2,4-dihy=droxy 0c propylphenylalanine, 2,5- dihydroxy-a-propylphenylalaline, and 2,6-di'hydroxy-apropylphenylalanine.

What is claimed is:

1. The process which comprises contacting N,N-dialkylhydroxybenzylamine with a lower alkyl ester of an a-nitroalkanoic acid to form the lower alkyl ester of a-alkyI-anitro-fi-hydroxyphenylpropionic acid, reducing said nitro ester to form an ester of an a-amino-a-hydroxybenzylalkanoic acid and hydrolyzing said ester to form an acalkyl-B-hydroxyphenylalanine.

2. The process which comprises contacting an N,N-dialkylhydroxybenzylamine with a lower alkyl ester of an a-nitroalkanoic acid to produce a lower alkyl ester of ualkyl-a-nitro-fi-hydroxyphenylpropionic acid.

3. The process which comprises contacting a compound of the formula wherein each of the R R and R substituents is a member selected from the group consisting of hydrogen, hydroxy, alkoxy, acyloxy, halogen and alkyl, at least one of said members being an hydroxyl substituent, each of the R substituents is a member selected from the group consisting of hydrogen, hydroxy, alkoxy, acyloxy, halogen, alkyl, amino, alkylamino and alkylthio, and the R sub- 16 stituents are selected from the group consisting of lower alkyl substituents and lower alkyl substituents joined in a heterocyclic ring selected from the group consisting of morpholine, piperidine and pyrrolidirie, with a lower alkyl ester of a-nitro'alkanoic acid to form an a nitro ester of the formula wherein R1, R2, R3 and R5 are as defined above and R is'a lower alkyl substituent, and subsequently contacting said a-nitro ester with Raney nickeland hydrogenatin'g said 'nitro ester in the presence of a catalyst selected from the group consisting of a noble metal, Raney nickel, aluminum amalgam and iron, tin or zinc in an acidic medium to form the corresponding amino ester and hydroly'zing said ester to form an amino acid of the formula T wherein each of the R R and R substituents is a member selected from the group consisting of hydrogen, hydroxy, alkoxy, acyloxy, halogen and alkyl, at least one of said members being an hydroxyl substituent, each of the R substituents is a member selected from the group consisting of hydrogen, hydroxy, alkoxy, acyloxy, halogen, alkyl, amino, alkylamino and alkylthio, and the R substituents are selected from the group consisting of lower alkyl substituents and lower alkyl substituents joined in a heterocyclic ring selected from the group consisting of morpholine, piperidine and pyrrolidine, with a lower alkyl ester of m-nitroalkanoic acid to produce a compound of the formula wherein R R R and R are as defined above and R is a lower alkyl substituent.

5. The process which comprises contacting p-hydroxy- N,N-dialkylbenzylamine with a lower alkyl ester of an anitroalkanoic acid to form a lower alkyl ester of a-alkyl-anitro-5-(p-hydroxyphenyl)propionate, contacting said alkyl propionate with Raney nickel and catalytically hydrogenating said product in the presence of a catalyst selected from a noble metal and Raney nickel to produce the corresponding amino ester and hydrolyzing said amino ester to produce an ot-alkyl-fl-(p-hydroxyphenyl)alanine.

6. T he process which comprises contacting N,N-dialkylp-hydroxybenzylamine with a lower alkyl ester of an anitroalkanoic acid in the presence of a catalytic amount c 7 of a strong base to form a lower alkyl ester of u-alkyl-anitro-fl-(p-hydroxyphenyl)propionate. V v [-7. The process which comprises contacting N,N-dial kyl- 3Qalkoxy-4-hydroxybenzylamine with a lower alkyl ester of an a-nitro alkanoic acid to produce a lower alkyl ester of a-nitro-fi-(3-alkoxy-4-hydroxyphenyl)propionic acid, hydrogenating said propionic acid ester in the presence of a catalyst selected from a noble metal and Raney nickel to produce the ester of a-alkyl-fi-(3-alkoxy-4-hydroxyphenyDalanine and contacting said phenylalanine compound with hydrobromic acid to produce an a-alkyl-B-3,4- dihyclroxyphenylalanine.

8. The process which comprises contacting N,N-dirnethyl-4-hydroxybenzylamine with an equimolar amount of ethyl a-nitropropionate and sodium hydride to produce ethyl 2-nitro-2-(p-hydroxybenzyl)propionate, heating said propionate ester inintimate contactwith aismall amount .of Raney nickel catalyst, separating said Raney nickel catalyst from said propionate ester and hydrogenating said propionate ester in the presence of a platinum oxide catalyst to produce the ethyl ester of u-methyltyrosine k which is hydrolyzed with acid or base to form a-methyltyrosine.

v9. The process which comprises contacting N,N.-dimethyl 3,4 dihydroxybenzylamine with an equimolar amount of ethyl -nitropropionate and sodium hydride to produce ethyl 2-nitro-2-(3,4-dihydroxybenzyl)propionate, heating said propionateester in intimate contact with a small amount of Raney nickel catalyst, separating said Raney nickel catalyst from said propionate ester and by? drogenating said 2-nitropropionate ester in the presence of a platinum oxide catalyst to form the corresponding aminopropionate ester and hydrolyzing said ester to form a-methyI-{B- 3,4-dihydroxyphenyl alanine.

, References Cited Organic Chemistry, by Finar (vol. I), 1963, page 565 relied on.

L ORRAINE A. WEINBERGER, Primary Examiner. L. AQ THAXTON, Assistant Examiner. 

